DESCRIPTION (Applicant's abstract): The fundamental goal of this proposal is to test the hypothesis that bulbospinal respiratory synaptic transmission expresses activity-dependent synaptic plasticity. Using an in vitro brainstem-spinal cord preparation from adult turtles as an experimental model, electrical stimulation will be applied to the spinal cord (C5) during reversible blockade of axonal conduction between brainstem and spinal cord (C3-C4). Evoked short-latency responses and endogenous respiratory motor output (before and after blockade) will be assessed with extracellular recordings from the ventral roots (C8). Based on preliminary data, we propose to test three specific hypotheses: (1) Low frequency stimulation of descending synaptic inputs to spinal motoneurons induces long-term depression of both evoked and spontaneous respiratory synaptic inputs; (2) High frequency stimulation of descending inputs to spinal motoneurons induces long-term potentiation of evoked and spontaneous respiratory synaptic inputs, but only when preconditions are satisfied by the activation of spinal serotonin receptors; and (3) Spinal long-term potentiation and depression are opposing processes whose expression depends on the relative activity of postsynaptic protein kinases and phosphatases, respectively. Our findings will yield insights into a potentially important mechanism that adjust (enhance or depress) synaptic inputs to respiratory motoneurons, thereby maintaining an appropriate drive to respiratory muscles. Perhaps more importantly, this will be one of the first experimental preparations that allow an assessment of plasticity in evoked synaptic responses with the relevant behavior (respiratory motor output). An understanding of the role played by neuromodulators (e.g., serotonin) and intracellular signalling pathways (kinases and phosphatases) that control such activity-dependent synaptic plasticity may provide the rationale to develop effective therapeutic approaches in patients with compromised respiratory function of spinal injuries.